MX2008016568A

MX2008016568A - Pharmaceutical compositions of memantine.

Info

Publication number: MX2008016568A
Application number: MX2008016568A
Authority: MX
Inventors: Julia Hrakovsky; Hagit Sebban
Original assignee: Teva Pharma
Priority date: 2006-07-05
Filing date: 2006-09-20
Publication date: 2009-01-19
Also published as: CN101528202A; EP1886670A1; NO20090554L; CA2654523A1; US20080008752A1; KR20090016611A; WO2008005036A1; RU2009103658A; BRPI0621789A2; IL195541A0; JP2009542647A

Abstract

The invention is directed to easily dissolved, stable dose proportional pharmaceutical compositions, comprising granulated memantine and methods of preparing the same. In particular, the invention is directed to granulated memantine pharmaceutical compositions in the form of film coated tablets.

Description

MEMORATE PHARMACEUTICAL COMPOSITIONS Cross Reference to Related Patent Applications The present invention claims priority of US Provisional Patent Application No. 60 / 818,823, filed July 5, 2006, which is incorporated herein by reference.

Field of the invention The invention relates to pharmaceutical compositions that are dose proportional, stable, easy to dissolve, comprising memantine, and methods of preparation thereof. In particular, the invention relates to pharmaceutical compositions granulated in the form of tablets coated with a film.

BACKGROUND OF THE INVENTION It is reported that memantine is an orally active N DA receptor antagonist. The memantine hydrochloride salt is commercially available as NAMENDA®. The name IUPAC reported for memantine hydrochloride is 3,5-dimethyladamantan-1-amine hydrochloride, memantine hydrochloride is also reported to be referred to by the chemical name of l-amino-3,5-dimethyladamantane hydrochloride. It is understood that memantine hydrochloride has the structural formula: The molecular formula of memantine hydrochloride is Ci3H2iN-HCl, and the molecular weight is 215.76.

Memantine HC1 is currently marketed by Forest in the form of tablets coated with a film under the trade name NAMENDA®. In Europe, memantine hydrochloride is marketed by Merz (AXURA®) and Lundbeck (EBIXA®). NAMENDA * has been approved by the United States Food and Drug Administration (FDA) for the treatment of Moderate to severe Alzheimer's. It is reported that NA ENDA film coated tablets contain memantine HCl and the following inactive ingredients: crystalline cellulose, lactose monohydrate, colloidal silicon dioxide, talc, magnesium stearate, hypromellose, triacetin, titanium dioxide, FD yellow & CN ° 6, FD blue &CN ° 2, and iron oxide black. US Publication No. 2006/0002999 A1 ("publication 999"), the teachings of which are incorporated herein by reference in its entirety, reports that pharmaceutical compositions of 1-aminocyclohexanes, such as memantine or neramexane, prepared by a method of direct compression, which are released at a dissolution speed of at least 80 percent in 60 minutes, and have a hardness of between 3 and 40 Kp, that is, between 4.2 and 56 SCU (Cobb Units) Resistant).

Although direct compression is a fairly simple process, in practice it has different disadvantages, for example, it needs a careful choice of ingredients to ensure fairly uniform particle sizes of all the ingredients, so that aggregation does not occur, and , therefore, the lack of homogeneity is a recurrent problem in direct compression compositions. In other words, the compositions prepared by direct compression processes have a lack of uniformity. Direct compression compositions usually require the use of ingredients that improve flow and compression aids, since the powders probably have poor flow, compressibility and bad adhesion, and "culmination", as revealed in the publication '999.

US Patent Application Publication No. 2006/0198884 Al ("publication x884"), the teachings of which are incorporated herein by reference in its entirety, reports pharmaceutical compositions of 1-aminocyclohexanes, such as memantine or neramexane. The terms used in this patent application are very unclear as to their precise definition, but this application would appear to claim different memantine dosage units comprising different amounts of memantine.

Extract of the invention The present invention relates to granular compositions comprising memantine, wherein 95 percent of the memantine is released within 60 minutes of being placed in 0.1 N HCl at 37 ° C. Preferably, 95 percent of the memantine is released within 45 minutes, more preferably within 30 minutes. minutes, and more preferably within 15 minutes since it is placed in 0.1 N HCl at 37 ° C.

Preferably, the memantine is in the form of memantine hydrochloride. More preferably, the memantine hydrochloride is present from 2 to 6 weight percent of the composition.

According to the invention, the granulated memantine composition preferably comprises memantine, and at least one pharmaceutically acceptable excipient. More preferably, memantine is memantine hydrochloride. Preferably, at least one pharmaceutically acceptable excipient is selected from the group consisting of diluents, binders, disintegrators, glidants, and lubricants. Preferred diluents include lactose monohydrate and microcrystalline cellulose.

Preferably, the diluent is present in an amount of 40 percent to 95 percent by weight of the composition. Preferred binders include povidone. Preferably, the binder is present in an amount of 0.5 percent to 10 percent by weight of the composition. Preferred disintegrants include croscarmellose sodium. Preferably, the binder is present in an amount of 3 percent to 10 percent by weight of the composition. Preferred glidants include colloidal silicon dioxide and talc.

Preferably, the glidant is present in an amount of 0.5 percent to 3 percent by weight of the composition. Preferred lubricants include magnesium stearate. Preferably, the lubricant is present in an amount of 0.5 percent to 2 percent by weight of the composition.

According to the invention, the composition of memantine or granulated memantine hydrochloride is preferably in the form of a solid oral dosage form. Preferably, the solid oral dosage form is a tablet or a capsule or a sachet of granules.

According to the invention, the granulated memantine composition is preferably in the form of a tablet coated with a film comprising memantine, lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and a coating . Again, memantine is preferably memantine hydrochloride.

The invention also relates to a wet granulation process for preparing a memantine composition comprising granular memantine and at least one pharmaceutically acceptable excipient, preferably a diluent, a binder and / or a disintegrator, in a liquid to form a granulate, and dry and grind the granulate. The granulate is then preferably used to form a composition which, for example, can then be compressed into tablet cores or filled capsules, such as by mixing with one or more excipients, preferably a disintegrator, a glidant and / or a lubricant. The granules can also be used "as they are", that is, as the granules without any further processing.

The invention also relates to a dry granulation process for preparing a memantine composition, which comprises mixing memantine and at least one excipient, preferably a diluent, a binder, a disintegrator, and / or a lubricant, to form a mixture, compact or form sheets with the mixture and grind the mixture to form granules. The granules are then preferably used to form a composition which, for example, can then be compressed into tablet cores or filled into capsules, for example by mixing with one or more excipients, preferably a disintegrator, a glidant, and / or a lubricant.

The invention also relates to a granulated menantin composition prepared by the wet granulation process.

The invention also relates to a granulated memantine composition prepared by a dry granulation process.

The invention also relates to the use of a composition of the invention in therapy. As discussed above, memantine has been approved for use in the treatment of Alzheimer's disease. Therefore, the compositions of the invention can be approved for the treatment of Alzheimer's disease. In a method of treating Alzheimer's disease, a therapeutically effective amount of the granulated memantine composition of the invention is administered to a patient in need thereof.

Detailed description of the invention The invention relates to the disadvantages of direct compression by providing memantine compositions prepared by granulation. The granulated memantine compositions of the invention have dissolution profiles comparable or better than those reported for direct compression compositions, without the need to increase the hardness of the compositions. tablets or prevent adhesion to punches or completion, as reported in the '999 publication. In addition, the hardness of the tablets has no substantial effect on the rate of dissolution. Granulation methods, particularly wet granulation, allow good uniformity of the active substance within the composition and very good stability of the finished product during the stability test under accelerated conditions (40"C and 75 percent relative humidity). ), as well as good fluency.

The invention provides a composition comprising memantine, prepared by granulation, wherein the granulation is preferably wet granulation. The granulated memantine composition of the invention is preferably an immediate release composition, wherein 95 percent of the memantine is released within 60 minutes of placing it in 0.1 N HCl at 37 ° C in a basket of 100 rpm (USP I apparatus). Preferably, 95 percent of the memantine is released within 45 minutes, more preferably within 30 minutes, and more preferably not less than 85 percent within 15 minutes of being placed in 0.1 N HCl at 37 ° C. in a basket at 100 rpm.

In wet granulation, the active ingredient is mixed, preferably together with excipients in powder form, and then mixed again in the presence of a liquid, usually water, which causes the powders to clump together into granules. The obtained granulate can be sieved and / or milled, dried and then sieved and / or milled to the desired particle size. The granulate can then be combined with additional excipients and / or formulated into a solid dosage form.

In the dry granulation, the active ingredient is mixed, preferably together with excipients in powder form, then compacted into sheets or a sheet or tape, and then crushed into compacted granules. The compacted granules can subsequently be formulated in a solid dosage form. Preferably, the dry granulation is carried out by roll compaction or "sheeting".

The composition of the invention may comprise memantine and at least one pharmaceutically acceptable excipient. Preferably, the composition comprises memantine, a diluent, a binder, a disintegrator, a glidant, a surfactant, a lubricant and a coating. Preferably, the memantine is in the form of memantine hydrochloride, which, more preferably, is present in an amount of between and 6 percent, preferably 3 and 5 percent by weight of the composition.

Useful diluents include diluents that are commonly used in solid pharmaceutical compositions. For example, useful diluents include, but are not limited to, at least one of calcium phosphate (dibasic and / or tribasic), calcium sulfate, cellulose powder, dextrates, dextrin, fructose, kaolin, lactitol, lactose, maltose , mannitol, microcrystalline cellulose, sorbitol, starch, and sucrose. Preferably, the diluent is at least one of lactose monohydrate or microcrystalline cellulose. More preferably, the diluent is present in an amount of 40 percent to 95 percent, preferably, 50 to 90 percent by weight of the composition.

Useful binders include binders commonly used in solid pharmaceutical compositions. For example, the binders include, but are not limited to, at least one of acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, maltose, methylcellulose, cellulose. microcrystalline, polyethylene oxide, starch, or povidone.

Although ethylcellulose can be used, the use of ethyl cellulose can hinder dissolution, and is not the most preferred binder. Preferably, the binder is povidone. More preferably, the binder is present in an amount of 0.5 percent to 10 percent, preferably, 1 to 5 percent by weight of the composition.

Useful disintegrators include those disintegrators commonly used in pharmaceutical compositions. For example, useful disintegrants include, but are not limited to, at least one of croscarmellose sodium, crospovidone, microcrystalline cellulose, potassium polacrilin, sodium starch glycolate, low substituted hydroxypropyl cellulose, and starch. Preferably, the binder is present in an amount of 3 percent to 10 percent by weight of the composition.

Useful glidants include glidants commonly used in solid pharmaceutical compositions. For example, useful glidants include, but are not limited to, at least one of silicon dioxide, magnesium trisilicate, cellulose powder, starch and talc. Preferably, the glidant is at least one of colloidal silicon dioxide and talc. More preferably, the glidant is present in an amount of 0.5 percent to 3 percent by weight of the composition.

Useful lubricants include those lubricants commonly used in solid pharmaceutical compositions. For example, useful lubricants include, but are not limited to, at least one of calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, lauryl sulfate, sodium, and zinc stearate. Preferably, the lubricant is magnesium stearate and / or sodium stearate fumarate and / or talc. More preferably, the lubricant is present in an amount of 0.5 percent to 2 percent by weight of the composition.

The composition can be formulated in a solid dosage form for oral administration. Preferably, the solid dosage form is a tablet, a capsule, or granules. More preferably, the solid dosage form is a tablet. More preferably, the solid dosage form is a tablet coated with a film.

In a particularly preferred embodiment, the composition is formulated in a film coated tablet comprising memantine hydrochloride, lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and a coating.

Preferably, the coating comprises Hypromellose, polyethylene glycol, Polysorbate, titanium dioxide and / or iron oxide. For example, the coating can be prepared from a commercially available powder mixture such as OPADRY®. OPAORY8, available in Colorcon, which normally comprises Hypromellose, Polyethylene Glycol, Polysorbate, and Dyes, for example titanium dioxide and iron oxide.

The invention also provides a process for preparing a memantine composition by wet granulation. The process comprises granulating memantine and at least one pharmaceutically acceptable excipient, preferably a diluent, a binder and a disintegrator, in a liquid to form a granulate. The granulate is then preferably dried and milled. The granulate is then preferably used to form a composition which, for example, can then be compressed into tablet cores or capsules can be filled, for example by mixing with one or more pharmaceutically acceptable excipients, preferably a disintegrator, a glidant or a lubricant.

The invention also provides a process for preparing a memantine composition by dry granulation. The process comprises mixing memantine and at least one pharmaceutically acceptable excipient, preferably at least one diluent, a binder, a disintegrator, and a lubricant to form a mixture, compact or form sheets with the mixture, and grind the sheets to form granules. The granules are then preferably used to form a composition which, for example, can then be compressed into tablet cores or filled capsules, for example by mixing with one or more pharmaceutically acceptable excipients, preferably a disintegrator, a glidant and a lubricant.

The compositions of the invention can be administered to a mammal. Preferably, the mammal is a human, and the composition is administered as pharmaceutical compositions. Preferably, the pharmaceutical composition is administered to treat Alzheimer's disease, according to the indications approved for NAMENDA®, see the prescription information.

The amount of memantine in a pharmaceutical composition is preferably an amount that can provide a therapeutically effective amount of memantine. It will be appreciated that the amount of memantine used differs according to the amount needed to produce the therapeutic response.

A "therapeutically effective" or "effective" amount of a drug or a pharmacologically active agent means an amount of the drug or agent that is non-toxic and sufficient to provide the desired effect, for example, the treatment of moderate to severe dementia of the type of Alzheimer's, if in fact memantine is useful for such treatment.

The amount of the memantine compound administered and the dosage regimen used depends on the particular compound selected, on the age and general condition of the subject being treated, on the severity of the subject's condition, and on the judgment of the attending physician. recipe.

As used herein, "treating", "treating" and "treating" means at least one of the following: reduction in the severity and / or frequency of symptoms, elimination of symptoms and / or cause underlying, - prevention of the onset of symptoms and / or their underlying cause, improvement or healing of damage. For example, the present method of "treating" Alzheimer's disease, as the term is used herein, then comprises both the prevention of the disorder in a predisposed individual and the treatment of the disorder in a clinically symptomatic individual. As discussed above, memantine has been approved for use in the treatment of Alzheimer's disease. Therefore, the compositions of the invention can be approved for the treatment of Alzheimer's disease.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those skilled in the art will appreciate modifications in the described and illustrated invention that do not depart from the spirit and scope of the invention disclosed in the specification. The following examples are given to help understand the invention, but are not intended and should be construed as limiting its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are known to those skilled in the art and are described in numerous publications.

Eg emplos Unless otherwise specified, the methods of analysis used were as follows: The dissolution was carried out in an assembly of 6 vessels, apparatus I (baskets) in a medium of 900 ml of 0.2 percent NaCl in 0.1 N HC1 at 37 ° with a rotation at 100 rpm. Sampling is at the specified times, followed by preparation by derivation with dansyl chloride. HPLC analysis using a fluorescence detector with a Ci8 column and a mobile phase of acetonitrile and water.

The assay is carried out using a CC apparatus equipped with an FID detector and an adhesive column of Rtx-5 amine 5 percent diphenyl-95 percent dimethyl polysiloxane and helium carrier gas. The auto-demirer and gradient parameters are detailed in the method. The sample is dissolved in a solution of potassium carbonate with sodium chloride, then extracted with hexane containing xylene as an internal standard. Standards and samples are injected into the GC column for a cycle time of up to 35 minutes.

Example 1: Composition of Memantine Prepared by Wet Granulation A mixture of memantine hydrochloride (5 mg / tablet), lactose monohydrate (70 mg / tablet), povidone (1 mg / tablet) and sodium croscarmellose (7 mg / tablet) [ Part I], was granulated with purified water as a granulating agent to form a granulate. The granulate was dried, sieved and mixed with a mixture of croscarmellose sodium (2 mg / tablet), microcrystalline cellulose (32.5 mg / tablet), and colloidal silicon dioxide (1 mg / tablet) [Part II] and magnesium stearate (1.5 mg / tablet) [Part III] to form a mixture.

The total mixing time was 30 minutes. The mixture was then compressed into tablet cores. The ingredients are summarized in Table 1.

Table 1: Ingredient (mg / tablet) Part I: Memantine HCl 5 Lactose Monohydrate 70 Povidone 1 Croscarmellose Sodium 7 Part II Croscarmellose Sodium 2 Microcrystalline Cellulose 32, 5 Colloidal Silicon Dioxide 1 Part III Magnesium Stearate 1.5 Total 120, 0 Example 2: Composition of Memantine Prepared by Wet granulation A mixture of memantine hydrochloride (10 mg / tablet), lactose monohydrate (140 mg / tablet), povidone (2 mg / tablet) and sodium croscarmellose (14 mg / tablet) [Part I], was granulated with purified water as granulation agent to form a granulate. The granulate was dried, milled and mixed with a mixture of croscarmellose sodium (4 mg / tablet), microcrystalline cellulose (65 mg / tablet), and colloidal silicon dioxide (2 mg / tablet) [Part II] and stearate of magnesium (3 mg / tablet) [Part III] to form a mixture. The total mixing time was 30 minutes. The mixture was then compressed into tablet cores. The ingredients are summarized in Table 2.

Table 2: Ingredient (mg / tablet) Part I: Memantine HC1 10 Lactose Monohydrate 140 Povidone 2 Croscarmellose Sodium 14 Part II Croscarmellose Sodium 4 Microcrystalline Cellulose 65 Colloidal Silicon Dioxide 2 Part III Magnesium Stearate 3 Total 240, 0 Example 3: Memantine Hydrochloride Prepared by Wet granulation A mixture of memantine hydrochloride (10 mg / tablet), lactose monohydrate (50 mg / tablet), microcrystalline cellulose (100 mg / tablet) and croscarmellose sodium (8 mg / tablet) [Part I], was granulated with purified water as granulation agent to form a granulate. The granulate was dried, sieved and mixed with a mixture of sodium of croscarmellose (4 mg / tablet), microcrystalline cellulose (60 mg / tablet), and talc (5 mg / tablet) [Part II] and magnesium stearate ( 3 mg / tablet) [Part III] to form a mixture. The total mixing time was 30 minutes. The mixture was then compressed into tablet cores. The ingredients are summarized in Table 3.

Table 3: Comparative Example 4: Composition of Memantine Hydrochloride Prepared by Direct Compression Memantine hydrochloride (5 mg / tablet), lactose monohydrate (55 mg / tablet), microcrystalline cellulose (55 mg / tablet), colloidal silicon dioxide (1 mg / tablet), talc (2.5 mg / tablet) and stearate of magnesium (1.5 mg / tablet) were sieved and mixed together to form a mixture. The mixing time of tablets and coated. The ingredients are summarized in Table 4 below.

Table 4 The pharmaceutical compositions prepared in Examples 1 and 2 were tested for testing and dissolution. The results are summarized in Table 5.

Table 5 The dissolution rate of the pharmaceutical composition prepared in Example 3 was tested using the USP Type I Apparatus (basket) with 900 m of 0.1 N HCl at 37 ° C and at a rotation speed of 100 rpm. The dosage profile of the pharmaceutical composition prepared in Example 3 is summarized in Table 6.

Table 6 Sample% Dissolved 15 30 45 60 minutes minutes minutes Example 3 (Hardness = 7 96 96 96 96 SCU) The pharmaceutical composition prepared in Examples 1 (wet granulation) and 4 (direct compression) were tested for uniformity of the mixture. The final mixture was sampled with ten samples taken from different places in the storage container, and all samples were tested for testing. The results are summarized in Table 7, where "RSD" refers to the relative standard deviation.

Table 7 The RSD limit for the sample of the invention of Example 1 is significantly less than the 5.0 percent that is acceptable to the FDA and 5.4 percent of Comparative Example 4. Therefore, as illustrated in the Table 7, the granulated memantine compositions of the invention prepared by wet granulation are within the acceptable limits of RSD, while those prepared by direct compression are outside the acceptable limits of RSD, ie they have a lack of uniformity.

In addition, as illustrated by the data presented above, the granulated memantine compositions of the present invention, preferably manufactured by wet granulation, have excellent physical and chemical characteristics. Furthermore, in view of the physical processing considerations, the preferred manufacturing method for memantine tablets was considered to be wet granulation. When wet granulation is used, there is no need to produce harder tablets to prevent adhesion, and there is no need to increase the mixing time to achieve good uniformity of the mixture.

Example 5: Composition of Memantine Prepared by Dry Granulation Memantine hydrochloride (5 mg / tablet), lactose monohydrate (35 mg / tablet), povidone (1 mg / tablet), croscarmellose sodium (7 mg / tablet), and magnesium stearate (0.5 mg / tablet) [Part I] are mixed to form a mixture. The mixture is then compacted or sheets are formed and then milled to form granules. The resulting granules are then mixed with croscarmellose sodium (2 mg / tablet), microcrystalline cellulose (32.5 mg / tablet), and colloidal silicon dioxide (1 mg / tablet) [Part II], and magnesium stearate (1 mg / tablet) [Part III] to form the composition. The total mixing time is 30 minutes. The ingredients are summarized in Table 8. Table 8 Ingredient (mg / tablet) Part I: Memantine HCl 5 Lactose Monohydrate 35 Microcrystalline Cellulose 35 Povidone 1 Croscarmellose Sodium 7 Magnesium Stearate 0.5 Part II Croscarmellose Sodium 2 Microcrystalline Cellulose 32, 5 Colloidal Silicon Dioxide 1 Part III Magnesium Stearate 1 OPADRY® 4 Total 124 Example 6: Composition of Memantine Prepared by Dry Granulation Memantine hydrochloride (10 mg / tablet), lactose monohydrate (50 mg / tablet), microcrystalline cellulose (100 mg / tablet), croscarmellose sodium (8 mg / tablet), and magnesium stearate (1 mg / tablet) [ Part I] are mixed to form a mixture. The mixture is then compacted or sheets are formed and then milled to form granules. The resulting granules are then mixed with croscarmellose sodium (4 mg / tablet), lactose monohydrate (50 mg / tablet), and talc (5 mg / tablet) [Part II], and magnesium stearate (2 mg / tablet) [ Part III] to form the composition. The total mixing time is 30 minutes. The ingredients are summarized in Table 9.

Table 9 Ingredient (mg / tablet) Part I: Memantine HC1 10 Lactose Monohydrate 50 Microcrystalline Cellulose 100 Croscarmellose Sodium 8 Magnesium Stearate 1 Part II Croscartnelose Sodium 4 Lactose monohydrate 60 Talc 5 Part III Magnesium Stearate 2 OPADRY® 8 Total 248 Dry granulation can be advantageous as an alternative for wet granulation if the chosen excipients are sensitive to water, or if aqueous processing is found to accelerate degradation processes. Several of the advantages attributed to compositions produced by wet granulation can be achieved using dry granulation by methods such as roller compaction or "sheeting".

While it is evident that the invention disclosed herein is well suited to meet the objectives set forth above, it will be appreciated that those skilled in the art can anticipate numerous modifications and embodiments. Accordingly, it is desired that the appended claims cover all those modifications and embodiments that are within the scope and spirit of the present invention.

Claims

1. A composition comprising granulated memantine.

2. A composition according to claim 1, comprising wet granular memantine.

3. A pharmaceutical dosage form, comprising the composition according to claim 1.

4. The pharmaceutical dosage form according to claim 3, wherein the dosage form has uniformity of content for a plurality of dosage forms, such that 10 dosage forms sampled individually have an average assay of between 90 and 100 percent of a desired value and a relative standard deviation of no more than 5.0 percent.

5. The pharmaceutical dosage form according to claims 3 and 4, wherein 95 percent of the memantine is released within 60 minutes of the placement of the dosage form in 900 ml of 0.1 N HCl at 37 ° C. in a basket apparatus that rotates at 100 rpm.

6. The pharmaceutical dosage form according to any of claims 3 to 5, wherein 95 percent of the memantine is released within 45 minutes from the placement of the dosage form in 0.1 N HCl.

7. The pharmaceutical dosage form according to any of claims 3 to 5, wherein 95 percent of the memantine is released within 30 minutes from the placement of the dosage form in 0.1 N HCl.

8. The pharmaceutical dosage form according to any of claims 3 to 5, wherein 95 percent of the memantine is released within 15 minutes from the placement of the dosage form in 0.1 N HCl.

9. The pharmaceutical dosage form according to any of claims 3 to 8, which also comprises at least one pharmaceutically acceptable excipient.

10. The pharmaceutical dosage form according to any of claims 3 to 9, wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluents, binders, disintegrants, glidants and lubricants.

11. The pharmaceutical dosage form according to any of claims 3 to 10, wherein the diluent is at least one of lactose monohydrate or microcrystalline cellulose.

12. The pharmaceutical dosage form according to any of claims 3 to 11, wherein the diluent is present in an amount of 40 percent to 95 percent by weight of the composition.

13. The pharmaceutical dosage form according to any of claims 3 to 12, wherein the binder is povidone.

14. The pharmaceutical dosage form according to any of claims 3 to 13, wherein the binder is present in an amount of 0.5 percent to 10 percent by weight of the composition.

15. The pharmaceutical dosage form according to any of claims 3 to 14, wherein the disintegrator is croscarmellose sodium.

16. The pharmaceutical dosage form according to any of claims 3 to 15, wherein the disintegrator is present in an amount of 3 percent to 10 percent by weight of the composition.

17. The pharmaceutical dosage form according to any of claims 3 to 16, wherein the glidant is at least one of colloidal silicon dioxide or talc.

18. The pharmaceutical dosage form according to any of claims 3 to 17, wherein the glidant is present in an amount of 0.5 percent to 3 percent by weight of the composition.

19. The pharmaceutical dosage form according to any of claims 3 to 18, wherein the lubricant comprises at least one of magnesium stearate, sodium stearyl fumarate and talc.

20. The pharmaceutical dosage form according to any of claims 3 to 19, wherein the lubricant is present in an amount of 0.5 percent to 2 percent by weight of the composition.

21. A tablet coated with a film, comprising the dosage form according to any of claims 3 to 20 and a coating.

22. The pharmaceutical dosage form according to any of claims 3 to 21, wherein the solid oral dosage form is a tablet, a capsule, or a sachet of granules.

23. The composition according to claim 1, wherein the granulated memantine is wet granulated memantine hydrochloride.

24. The composition according to claim 1, wherein the granulated memantine is granulated memantine hydrochloride.

25. The composition according to claim 24, wherein the granulated memantine hydrochloride is present in an amount of 2 to 6 weight percent of the composition.

26. The composition according to claims 24 and 25, which also comprises lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

27. The pharmaceutical oral dosage form of memantine hydrochloride, which comprises the composition according to any of claims 24 to 26.

28. The dosage form according to claim 27, wherein the memantine HCl is present in an amount of 5 mg, the lactose monohydrate is present in an amount of 70 mg, the povidone is present in an amount of 1 mg, the Croscarmellose sodium is present in an amount of 9 mg, microcrystalline cellulose is present in an amount of 32.5 mg, colloidal silicon dioxide is present in an amount of 1 mg, and magnesium stearate is present in an amount 1.5 mg.

29. The dosage form according to claim 27, wherein the memantine HCl is present in an amount of 10 mg, the lactose monohydrate is present in an amount of 140 mg, the povidone is present in an amount of 2 mg, the Croscarmellose sodium is present in an amount of 18 mg, the microcrystalline cellulose is present in an amount of 65 mg, the colloidal silicon dioxide is present in an amount of 2 mg, and magnesium stearate is present in an amount of 3 mg.

30. A wet granulation process for preparing a memantine composition, which comprises granulating memantine HC1 with a liquid to form a granulate, drying and grinding the granulate, and forming a composition from the granulate.

31. The process according to claim 30, wherein the liquid is water.

32. The process according to any one of claims 30 and 31, which also comprises mixing the memantine with at least one pharmaceutically acceptable excipient before the granulation with the liquid.

33. The process according to any of claims 30 to 32, which also comprises mixing the granulate with at least one pharmaceutically acceptable excipient to form the composition.

34. The process according to claim 33, wherein the additional pharmaceutically acceptable excipient is selected from the group consisting of diluents, glidants, disintegrators and lubricants.

35. A dry granulation process for preparing a memantine composition, comprising compacting or forming memantine sheets, grinding the compact or resulting sheets to form granules, and forming a composition from the granules.

36. The process according to claim 35, which also comprises mixing the memantine and at least one pharmaceutically acceptable excipient to form a mixture, before compaction or sheet formation.

37. The process according to any of claims 35 and 36, wherein the composition is formed from the granules by mixing the granulate with at least one additional pharmaceutically acceptable excipient.

38. The process according to claim 37, wherein the additional pharmaceutically acceptable excipient is selected from the group consisting of diluents, glidants, disintegrators and lubricants.

39. The solid dosage form according to any of claims 3 to 20 and 27 to 29, prepared by a process comprising granulating memantine, granulating menannin and at least one pharmaceutically acceptable excipient in a liquid to form a granulate, dry and grind the granulate and form the composition from the granulate.

40. The solid dosage form according to claim 39, wherein the liquid is water

41. The solid oral dosage form according to any of claims 3 to 20 and 27 to 29, prepared by a process comprising mixing memantine and at least one pharmaceutically acceptable excipient to form a mixture, compact or form sheets with the mixture, grind the mixture to form granules and form the composition from the granules.

42. The use of the dosage form according to any of claims 3 to 20 and 27 to 29 for the treatment of Alzheimer's disease.